Glycosylphosphatidylinositol (GPI) structures are ubiquitous in nature—they occur in almost all organisms except eubacteria, and roughly 0.5% of all proteins are expected, based on genomic analysis, to be linked to the cell surface via GPI anchors.1 Many organisms, especially protozoa, also express non-protein-linked GPI-type glycans on their cell surfaces; these are often essential for virulence, immune evasion, and other important properties.2 In addition to their structural functions, GPI molecules serve as intermediate messengers in signal-transduction pathways involving hormones, cytokines, and growth factors.3 GPIs are especially important because of their roles in tropical diseases such as malaria and typanosomiasis,2 genetic disease,4 diabetes,3 and cancer.5 
GPIs have substantial structural similarity, with a conserved Man(α1→2)Man(α1→6)Man(α1→4)GlcN(α1→6)myo-iositol core structure attached to protein via an ethanolamine phosphate on the 6-OH of the terminal mannose and to the outer membrane leaflet via a lipid on the 1-OH of inositol.1 A given GPI may consist of this core only, or be decorated with saccharides or other moieties; for example, mammalian GPIs have additional phosphoethanolamine, whereas protozoa lack this modification. As many different functionalizations are possible, GPIs found in nature are usually highly heterogeneous.6 
The difficulty of purifying polyfunctional molecules such as GPIs from natural sources, the paucity of different structures thus available, and the inevitable heterogeneity of the material isolated suggest chemical synthesis as a general solution to the application of GPIs.
Accordingly, GPIs have attracted the attention of synthetic organic chemists since their discovery, resulting in a number of syntheses. The ceramide-containing GPI anchor of yeast (Saccharomyces cerevisiae),7 acylglycerol containing GPI anchor of Trypanosoma brucei,8 and rat brain Thy-19 have all been completed in the last ten years using a variety of methodologies and protecting group combinations. In addition, GPI structures have been prepared for biological studies aimed at elucidating the insulin signaling pathway.10 
Müller et al. have reported a synthesis using a.10 See FIG. 1A and FIG. 1B. This route is non-convergent, making modification more difficult; it suffers from a dependence on protecting-group manipulations on large structures, which results in loss of more valuable material; and the protecting-group combinations used (esp. the TBS and isopropylidine) are incompletely orthogonal and restrict the diversity of structures possible.
Schmidt et al. have reported a method using k.11 See FIG. 2A and FIG. 2B. This synthesis, much like the one mentioned previously, shows some similarity to our methods, indicating a limited degree of consensus among GPI chemists. See the extended commentary, infra, for analysis.
Martin-Lomas et al. used v as an intermediate.10 See FIG. 3. Their method uses a variety of protecting group-patterns requiring late-stage manipulation; it also lacks the flexibility to install phosphate moieties in the natural manner (or at all), thus limiting the utility for making structures recognized by biological systems.
Fraser-Reid et al. have made cc, which incorporates many robust and generally useful protecting-group patterns.12 See FIG. 4A and FIG. 4B. The principal drawback to this route is the near-exclusive use of n-pentenyl glycoside donors, developed by the group; although these do provide acceptable results, their lack of adoption by the carbohydrate-synthesis community at large is testament to the difficulty of applying them successfully. Our method uses more common techniques which are reliable even when applied by less-skilled operators.
Similarly, many of the protection schemes used by Ley et al. in oo are intended to demonstrate a new technology rather than produce optimal results or versatility.8 See FIG. 5. Although the generation of large structures is possible, our simple, general methods provide greater opportunities for easy modification of the synthesis, minimize the chances of protecting-group incompatibility, and make deprotection of the final structures simpler.